The overall goal of this Program Project is to test the hypothesis that mutations in the genes that encode for the extracellular components of articular cartilage. In particular for the collages of the tissue cause certain forms of heritable osteoarthritis in man. Our research will focus on three diseases that produce degeneration of articular cartilage and that show a dominant pattern of Mendelian inheritance: (1) familial primary generalized osteoarthritis; (2) familial chondrocalcinosis; and (3) Wagner- Stickler's syndrome or arthro-ophthalmopathy. The hypothesis is supported by data from RFLP analyses that indicate that the type 11 procollagen gene is the gene at fault in a large family with primary generalized osteoarthritis and in a second family with arthro-ophthalmopathy. The hypothesis will be tested with a number of innovative approaches. Including the latest techniques of cell biology, biochemistry and molecular biology, some of these developed within our own laboratories. The methods have been extensively and successfully used by our group for the identification of the genetic mutations that cause osteogenesis imperfecta and Ehlers-Danlos syndrome. The proposal contains five complementary and inter-related projects representing a truly multi-disciplinary approach involving recognized experts in the Fields of clinical rheumatology. Orthopedic surgery, cartilage biochemistry cell and developmental biology and molecular biology. Through the experiments proposed here. We will define the exact molecular causes of the diseases and establish whether or lot these diseases are single entities at the molecular level. The results will also provide simple OA tests for definitive diagnosis of the molecular defects in individual patients. The same tests can be used to establish whether or not more common forms of OA are caused by the same mutations. A series of important consequences with flow for the experiments in which mutated genes are used to produce transgenic mice. These studies will provide fundamental information about the structure-function relationships of type II procollagen at both the gene and protein level that cannot be obtained in any other way and will provide an autheatic model for human OA that will be useful for drug testing and for all future considerations of gene therapy in man.